Pharmaceutical composition containing a mitophagy inducer

Abstract

The present invention relates to a pharmaceutical composition containing a mitophagy inducer as an active ingredient. The pharmaceutical composition is advantageous for the manufacture of pharmaceutical formulations, avoids the occurrence of incompatibility due to interactions between the active ingredient and auxiliary agents, and allows for long-term storage.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing a mitophagy inducer and belongs to the field of pharmaceutical formulations. [Background technology]

[0002] The compound of formula I and its specific compound (in particular TJ0113) are described in CN115894404A and are mitophagy inducers that can be used to suppress or alleviate various acute or chronic diseases caused by mitophagy dysfunction. The general formula and the structure of compound TJ0113 are as follows.

[0003] Prior art (TIFF2026511338000001.tif66170) does not include any research on pharmaceutical compositions or formulations of the compound in question. The inventors of this application have found that mitophagy-inducing compounds are prone to stability problems during formulation, and this is because the compounds readily interact with various adjuvants commonly used in the pharmaceutical industry, resulting in incompatibility and making them unsuitable for long-term storage. Therefore, in this technical field, there is an urgent need to develop pharmaceutical compositions that solve the problem of incompatibility between the mitophagy-inducing compound and the adjuvants, and to obtain formulations that can be stored for a long period of time. [Overview of the project]

[0004] The inventors of this application have conducted extensive research to solve the above problems and have developed a pharmaceutical composition containing a mitophagy inducer that can overcome the problem of incompatibility. Specifically, the present invention includes, but is not limited to, the following technical solutions.

[0005] 1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, or a lubricant, but not containing any of hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, colloidal silica, magnesium stearate, talc powder, mannitol, or cross-linked carboxymethylcellulose sodium, TIFF2026511338000002.tif31170式中、R 2 is hydrogen, C 1~4 alkyl, C 3~6 cycloalkyl, or a 4- to 6-member epoxyalkyl; R 3 is TIFF2026511338000003.tif19170; wherein, R 3-1 is hydrogen, hydroxyl, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, a 3- to 6-member epoxyalkyl, -N(R 3-2 R 3-2a ), -CH2C(O)R 3-2 ), -CH2C(O)OR 3-2 ), -CH2C(O)NR 3-2 R 3-2a ; and[[ID=三十五]] R 3-2 and R 3-2a are each independently hydrogen, C 1~4 alkyl or a 3- to 6-member cycloalkyl, Ar is phenyl, a 5- or 6-member monocyclic heteroaryl, or a 5- or 6-member monocyclic heteroaryl substituted with at least one R 3-3 ; where the R 3-3 is hydrogen, halogen, C 1~4 alkyl, a 3- to 6-member cycloalkyl, hydroxyl, C 1~4 alkoxy, a 3- to 6-member epoxyalkyl, C 1~4 haloalkyl, C 2~4 alkenyl, C 2~4 alkynyl, -N(R 3-3a R 3-3b ), or phenyl; R 3-3a and R 3-3b are each independently hydrogen, C 1~4 alkyl or a 3- to 6-member cycloalkyl; R 4 is TIFF2026511338000004.tif24170, wherein, R 4-1is phenyl, at least one R 4-11 Phenyl substituted with, 5-membered or 6-membered monocyclic heteroaryl, at least one R 4-11 A 5- or 6-membered monocyclic heteroaryl substituted with, an 8- to 10-membered fused bicyclic heteroaryl, or at least one R 4-11 It is an 8- to 10-membered condensed bicyclic heteroaryl substituted with, where R 4-11 is halogen, nitro group, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, or TIFF2026511338000005.tif16170, R 4-1a and R 4-1b Each is independently hydrogen and C 1~4 Alkyl or C 3~6 It is cycloalkyl, R 4-1a and R 4-1b They may be joined to each other to form a ring. R 4-2 C 1~4 Alkyl, C 3~6 It is cycloalkyl, or R 2 C 1~4 If it is alkyl, R 4-2 is R 2 It bonds to form a 4-8 membered ring, R 4-3 is C 1~4 Alkyl or C 1~4 It is an alkoxy; R 5 The number of R is 0 to 5. 5 If the number is not 0, each R 5 These are, independently, halogen, nitro group, nitrile group, and -N. + (R 5-1 )3, C 1~4 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 ,-C(O)N(R 5-1 R 5-1a)、 -S(O)2R 5-1 、 -S(O)R 5-1 、 -N=C(R 5-1 R 5-1a )、 hydroxy, C 1~4 alkyl, phenyl, phenyl in which at least one hydrogen is replaced by R 5-1 and C 1~4 alkoxy, -N(R 5-1 R 5-1a )、 -N(R 5-1 )C(O)R 5-1a 、 -OC(O)R 5-1 、 -OC(O)N(R 5-1 R 5-1a )、 or -SR 5-1 selected from, where R 5-1 、 R 5-1a and R 5-1b are each independently hydrogen, C 1~4 alkyl, C 2~4 alkenyl, C 2~4 alkynyl, C alkyl in which at least one hydrogen is replaced by halogen 1~4 、 C alkenyl in which at least one hydrogen is replaced by halogen 2~4 、 or C alkynyl in which at least one hydrogen is replaced by halogen 2~4 characterized in that it is a pharmaceutical composition.

[0006] 2. The diluent contains microcrystalline cellulose and pregelatinized starch, the pharmaceutical composition according to Technical Solution 1.

[0007] 3. The disintegrant is sodium carboxymethyl starch, the pharmaceutical composition according to Technical Solution 1 or 2.

[0008] 4. The lubricant is sodium stearyl fumarate, the pharmaceutical composition according to any one of Technical Solutions 1 to 3.

[0009] 5. R 2 is hydrogen or C 1~4 alkyl; R 3 is TIFF2026511338000006.tif19170; Here, R 3-1 is hydrogen, hydroxyl, C 1~4 alkyl or C 1~4 alkoxy, R 4 is TIFF2026511338000007.tif24170, Here, R 4-1 is phenyl, phenyl substituted with at least one R 4-11 , 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heteroaryl substituted with at least one R 4-11 , 8- to 10-membered fused bicyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl substituted with at least one R 4-11 , wherein the R 4-11 is halogen, nitro group, C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~4 haloalkyl, C 1~4 haloalkoxy or TIFF2026511338000008.tif16170, and R 4-1a and R 4-1b are each independently hydrogen, C<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​If the number is not 0, each R5 is independently a halogen, a nitro group, a nitrile group, and -N + (R 5-1 )3, C 1~4 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 ,-C(O)N(R 5-1 R 5-1a ), -S(O)2R 5-1 ,-S(O)R 5-1 -N=C(R 5-1 R 5-1a ), hydroxyl, C 1~4 Alkyl, phenyl, at least one hydrogen is R 5-1 Phenyl substituted with C 1~4 Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a -OC(O)R 5-1 ,-OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 Selected from, where R 5-1 , R 5-1a and R 5-1b Each is independently hydrogen and C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkynyl, a C atom with at least one hydrogen atom substituted with a halogen. 1~4 Alkyl, C in which at least one hydrogen is substituted with a halogen. 2~4 C19 is an alkenyl or at least one hydrogen atom is substituted with a halogen. 2~4 A pharmaceutical composition that is alkynyl, as described in any of technical solutions 1 to 4.

[0010] 6.R 2 is hydrogen or C 1~4 It is alkyl, R 3 teeth TIFF2026511338000009.tif19170, R 3-1 is hydroxy or C 1~4 It is an alkoxy, R 4 teeth The filename is TIFF2026511338000010.tif20170. Here, R 4-1 is phenyl, at least one R 4-11 Phenyl substituted with, 5-membered or 6-membered monocyclic heteroaryl, or at least one R 4-11 A 5-membered or 6-membered monocyclic heteroaryl substituted with the R 4-11 is halogen, nitro group, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkyl; and R 5 The pharmaceutical composition described in technical solution 5, wherein the number is 0.

[0011] 7.R 2 It is hydrogen, R 3 teeth The filename is TIFF2026511338000011.tif20170, and R 3-1 It is hydroxyl, R 4 teeth The filename is TIFF2026511338000012.tif20170. Here, R 4-1 is at least one R 4-11 A phenyl substituted with the R 4-11 is halogen, C 1~4 Alkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkyl; and R 5 The pharmaceutical composition according to technical solution 6, wherein the number is 0.

[0012] 8. The compound of formula I is TJ0113, a pharmaceutical composition as described in technical solution 7.

[0013] TIFF2026511338000013.tif341709. The pharmaceutical composition according to technical solution 8, wherein TJ0113 is a solid form of a sodium salt represented by the following formula. TIFF2026511338000014.tif35170

[0014] (In the formula, X is between 0.1 and 2, for example, 1).

[0015] 10. The pharmaceutical composition according to technical solution 9, wherein the powder X-ray diffraction pattern of the solid form shows characteristic peaks (CuKα lines) at 2θ of 7.06° (±0.2°) and 20.87° (±0.2°).

[0016] 11. A pharmaceutical composition according to any one of technical solutions 1 to 10, comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

[0017] 12. A pharmaceutical composition according to technical solution 11, comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

[0018] 13. A pharmaceutical composition according to any one of technical solutions 1 to 12, wherein the percentage of compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1.0% to 50% by weight, the percentage of diluent in the pharmaceutical composition is 30% to 90% by weight, the percentage of disintegrant in the pharmaceutical composition is 0.1% to 25% by weight, and the percentage of lubricant in the pharmaceutical composition is 0.01% to 5.0% by weight.

[0019] 14. A pharmaceutical formulation comprising a pharmaceutical composition described in any of Technical Solutions 1 to 13, wherein the pharmaceutical formulation is selected from tablets, capsules, granules, powders, and pills.

[0020] 15. The pharmaceutical preparation according to technical solution 14, wherein the pharmaceutical preparation is a capsule comprising a capsule shell and contents, and the contents are a pharmaceutical composition according to any one of technical solutions 1 to 13.

[0021] Preferably, in the proposed technical method relating to the solid form of the sodium salt of compound TJ0113, the powder X-ray diffraction pattern shows characteristic peaks at at least one 2θ selected from 7.06°(±0.2°), 18.07°(±0.2°), 25.02°(±0.2°), 17.58°(±0.2°), 20.87°(±0.2°), 10.54°(±0.2°), and 23.91°(±0.2°). More preferably, the solid form of the sodium salt of the compound of formula I exhibits a characteristic peak at at least one (more preferably at least two, even more preferably at least three) 2θ selected from 7.06°(±0.2°), 18.07°(±0.2°), 25.02°(±0.2°), 17.58°(±0.2°), 20.87°(±0.2°), 10.54°(±0.2°), 23.91°(±0.2°), 27.65°(±0.2°), 27.05°(±0.2°), 21.68°(±0.2°), and 25.91°(±0.2°) in the powder X-ray diffraction pattern. More preferably, the solid form of the sodium salt of the compound of formula (I) (also referred to herein as "crystalline form D") exhibits a powder X-ray diffraction pattern substantially identical to that of Figure 8.

[0022] The solid form of crystalline form D of the sodium salt of compound TJ0113 shows an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C (±3°C) in its differential scanning calorimetry curve. The solid form of the sodium salt of the compound of formula (I) of the present invention exhibits a thermogravimetric analysis (DSC) curve spectrum substantially identical to that shown in Figure 9.

[0023] In some preferred embodiments, the thermogravimetric analysis curve of the solid form of crystalline form D of the sodium salt of compound TJ0113 exhibits a thermogravimetric analysis spectrum substantially identical to that shown in Figure 10.

[0024] In some preferred embodiments, the pharmaceutical composition comprises the following parts by weight of the following components: Compound of general formula (I) or a pharmaceutically acceptable salt thereof...20-30 parts; Diluent... 50-80 parts; Disintegrant... 1-10 units; Lubricant... 0.1 to 3 parts.

[0025] In some preferred embodiments, the pharmaceutical composition comprises the following parts by weight of the following components: Compound of general formula (I) or a pharmaceutically acceptable salt thereof...23-28 parts; Diluent... 60-70 parts; Disintegrant... 3-8 parts; Lubricant... 0.1 to 1 part.

[0026] In some preferred embodiments, the diluent is at least one selected from microcrystalline cellulose, lactose, mannitol, starch, and dextrin.

[0027] In some preferred embodiments, the disintegrant is at least one selected from carboxymethyl starch sodium, crosslinked carboxymethylcellulose sodium, and crosslinked polyvinylpyrrolidone.

[0028] In some preferred embodiments, the lubricant is at least one selected from magnesium stearate, sodium stearyl fumarate, and talc powder.

[0029] In some preferred embodiments, the pharmaceutical composition may further contain a thickener (e.g., gelatin, gelatin arabic), a preservative (e.g., benzoate, sorbate), a binder (e.g., a mixture of powdered sugar and syrup, polyvinylpyrrolidone), a sweetener (e.g., sucrose, aspartame), a stabilizer (e.g., ascorbic acid, sodium thiosulfate), and / or a fluidizing agent (e.g., colloidal silica, talc powder).

[0030] In some preferred embodiments, the diluent is microcrystalline cellulose and pregelatinized starch.

[0031] In some preferred embodiments, the disintegrant is sodium carboxymethyl starch.

[0032] In some preferred embodiments, the lubricant is sodium stearyl fumarate. [Brief explanation of the drawing]

[0033] [Figure 1] Figure 1 shows the effect of the type of diluent on the elution results in Example 2 (paddle method + sedimentation basket, 50 rpm). [Figure 2] Figure 2 shows the effect of the diluent ratio on the elution results in Example 2 (basket method, 75 rpm). [Figure 3] Figure 3 shows the effect of the type of disintegrant on the elution results in Example 3 (basket method, 75 rpm). [Figure 4] Figure 4 shows the effect of the solubilizer on the elution results in Example 3 (basket method, 75 rpm). [Figure 5] Figure 5 shows the dissolution experiment results for the 20 mg capsule in Example 3 (paddle method + sedimentation basket, 75 rpm). [Figure 6] Figure 6 shows the dissolution results of a 20 mg capsule of F14 in Example 4 (paddle method + sedimentation basket, 75 rpm). [Figure 7] Figure 7 shows the stability dissolution results of 100 mg capsules of F13 in Example 4 (paddle method + sedimentation basket, 75 rpm). [Figure 8] Figure 8 shows the powder X-ray diffraction pattern of crystalline form D of the sodium salt of compound TJ0113. [Figure 9] Figure 9 shows the differential scanning calorimetry curve spectrum of crystalline form D of the sodium salt of compound TJ0113. [Figure 10] Figure 10 shows the thermogravimetric analysis curve spectrum of crystalline form D of the sodium salt of compound TJ0113. [Figure 11] Figure 11 shows the XRPD spectra of the sample before and after dry granulation in Example 5. [Modes for carrying out the invention]

[0034] Compounds of formula I or pharmaceutically acceptable salts thereof (e.g., compound TJ0113) are also referred to herein as “active ingredient” or “API”. Those skilled in the art will understand that compounds of formula I have similar structures and therefore similar properties, and that any compound within that range is applicable to the formulations defined in this invention.

[0035] As detailed in the experimental details of the examples, the inventors of this application have discovered incompatibility issues between the active ingredient and the auxiliary agents hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, colloidal silica, magnesium stearate, talc powder, sugar alcohols (especially mannitol), and cross-linked carboxymethylcellulose sodium. Therefore, the formulation of the present invention does not contain these auxiliary agents that cause incompatibility issues.

[0036] In the pharmaceutical composition of the present invention, the percentage of active ingredient content in the pharmaceutical composition may be, for example, 1.0% to 50% by weight, for example 1.0% to 2.0% by weight, 5.0% by weight, 8.0% by weight, 10.0% by weight, 12% by weight, 15% to 25% by weight, 30% by weight, 35% by weight, 40% by weight, or 50% by weight, for example 10.0% to 40% by weight, or 16% to 30% by weight, preferably 20% to 25% by weight, or about 25% by weight.

[0037] Diluents refer to auxiliary agents used to increase the volume or weight of solid pharmaceutical preparations, and are also called fillers. Except for auxiliary agents that cause the compatibility problems described above, the pharmaceutical composition of the present invention may contain diluents known in the art, such as lactose, microcrystalline cellulose, and pregelatinized starch. From the viewpoint of promoting dissolution, a mixture of microcrystalline cellulose and pregelatinized starch is preferred, and for example, the percentage of each substance that has been demonstrated by experiments in the examples does not have a large effect on the dissolution effect, and may be, for example, 5:1 to 0.5:1, preferably 3:1 to 1:1. The percentage of diluent content in the pharmaceutical composition may be, for example, 30% to 90% by weight, for example, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70% to 75%, 80%, 85%, 90%, for example, 40% to 85%, or 55% to 80%, preferably 65% ​​to 75%, or about 70%, where, The percentage of pregelatinized starch in the pharmaceutical composition may be, for example, 1.0% to 50% by weight, such as 1.0%, 2.0%, 5.0%, 8.0%, 10.0%, 12%, 15% to 25%, 30%, 35%, 40%, or 50% by weight, such as 10.0% to 30% or 12% to 30%, preferably 15% to 25% by weight. Examples of diluents used in this application include commercially available microcrystalline cellulose 102 (purchased from Microcellulose Weissenborn GmbH + Co.KG) and pregelatinized starch STARCH 1500 (registered trademark) (purchased from Colorcon).

[0038] A disintegrant refers to an auxiliary agent used to promote the rapid disintegration of a solid dosage form into fine particles in a digestive fluid. Except for auxiliary agents that cause the compatibility issues described above, the pharmaceutical composition of the present invention may contain disintegrants known in the art, such as sodium carboxymethyl starch. The percentage of disintegrant content in the pharmaceutical composition may be, for example, 0.1% to 25% by weight, such as 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 2.7% to 3.0%, 3.2%, 3.5%, 4.0%, 5.0%, 7%, 8.0%, 10.0%, 12%, 15%, 20%, or 25%, and may also be, for example, 0.5% to 7%, or 1.0% to 5%, preferably 2.5% to 3.5%, or about 3% by weight. Examples of disintegrants used in this invention include commercially available cross-linked carboxymethylcellulose sodium SD711 (purchased from DuPont Nutrition USA Inc.).

[0039] A lubricant refers to an auxiliary agent that reduces friction between particles and improves the fluidity of powders, thereby reducing differences in weight and active ingredient content between formulations. While magnesium stearate and talc powder are commonly used lubricants in the pharmaceutical industry, the inventors have found that both of these are auxiliary agents that cause compatibility issues. Therefore, the pharmaceutical compositions of this invention require the use of other lubricants, such as sodium stearyl fumarate. The lubricant in this application may be added internally or externally. Internal addition refers to addition during particle preparation to ensure uniform component content between particles, while external addition refers to addition between particles prepared to ensure a uniform number of particles in each formulation unit. Unless otherwise specified, the lubricant content described herein refers to the total content of internally and externally added lubricants. The percentage of lubricant in the pharmaceutical composition may be, for example, 0.01% to 5.0% by weight, such as 0.01%, 0.1%, 0.2%, 0.3%, 0.5% to 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, or 5.0%, such as 0.1% to 2.0%, or 0.2% to 1.5%, preferably 0.5% to 1.0%, or about 1% by weight. The lubricant used in this application is, for example, commercially available sodium stearyl fumarate (purchased from Moehs Cantabra).

[0040] Furthermore, the pharmaceutical composition of the present invention may contain other types of auxiliary agents as needed, as long as they do not belong to the category of auxiliary agents that cause the aforementioned compatibility problems.

[0041] Furthermore, the pharmaceutical composition of the present invention may optionally contain other types of excipients, such as binders, colorants, flavoring agents, wetting agents, preservatives, and solubilizers.

[0042] The present invention also relates to pharmaceutical formulations comprising the pharmaceutical composition described herein, wherein the pharmaceutical formulation is a solid pharmaceutical formulation known in the art, such as a tablet, capsule, granule, powder, or pill. The pharmaceutical formulation may contain other components known in the art in addition to the pharmaceutical composition. For example, in the case of a tablet, the formulation may have a coating in addition to the pharmaceutical composition, and in the case of a capsule, the formulation may have a capsule shell in addition to the pharmaceutical composition. The aforementioned coating or capsule shell may be a coating known in the art (e.g., a film coating, a release-controlled coating) or a capsule shell (e.g., a gelatin capsule shell), respectively, and both can be obtained using methods known in the art.

[0043] The pharmaceutical compositions and pharmaceutical preparations according to the present invention can be manufactured by conventional methods in the art. For example, in the case of granules, they can be manufactured using methods known in the art, such as dry granulation and wet granulation. Furthermore, the granules can be further compressed into tablets or filled into capsule shells to form capsules.

[0044] The terms "halogen" and "halo" in this invention include fluorine, chlorine, bromine, and iodine.

[0045] As used herein, the term "approximately" indicates a range of 10% above or below the corresponding value. For example, if the concentration of a component is approximately 5 mM, it indicates that the concentration is between 4.5 and 5.5 mM. If the concentration range of a component is approximately 5 to 10 mM, it indicates that the concentration range is between 4.5 and 11 mM. Unless otherwise specified, percentages used herein are weight percentages (wt%) and are usually expressed based on the total weight of the pharmaceutical composition or preparation.

[0046] In some preferred embodiments, the solid form (particularly crystalline form D) of the sodium salt of the TJ0113 compound is prepared by the following method: obtaining the TJ0113 compound (for example, by the method described in Prior Art CN115894404A), then dissolving the TJ0113 compound in a reaction medium and adding a sodium-containing base to react with it.

[0047] In some preferred embodiments, the reaction medium is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate, or a mixture of at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate with water. Examples include acetone, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0048] In some preferred embodiments, the sodium-containing base is selected from at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium acetate, sodium formate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0049] In some preferred embodiments, the molar ratio of the TJ0113 compound to the sodium-containing base in the reaction system is 1:(0.9~1.1).

[0050] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C (preferably 40-50°C), a sodium bicarbonate solution is added, and after the solid precipitates, it is kept warm and allowed to stand for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain the solid form of the sodium salt of the TJ0113 compound.

[0051] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, cooled to room temperature, then sodium bicarbonate solution is added and stirred until a solid precipitate forms. After this, the mixture is kept warm for at least 20 minutes (preferably at least 30 minutes) to allow it to stand, thereby obtaining the solid form of the sodium salt of the TJ0113 compound.

[0052] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a sodium bicarbonate solution is added and stirred, and after the solid precipitates, the mixture is kept warm and stirred for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain the solid form of the sodium salt of the TJ0113 compound.

[0053] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a methanol solution of sodium methoxide is added and stirred, and after the solid precipitates, it is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes), then cooled to room temperature and stirred for at least 50 minutes (preferably at least 60 minutes) to obtain the solid form of the sodium salt of the TJ0113 compound.

[0054] In some preferred embodiments, the TJ0113 compound is dissolved in acetone at 35-55°C, a sodium bicarbonate solution is added and stirred until a solid precipitate forms, then the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes), and then kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes) to obtain the solid form of the sodium salt of the TJ0113 compound.

[0055] The following preparation examples illustrate methods for producing the crystalline form D, and all of the TJ0113 compounds are obtained by the method described in Prior Art CN115894404A.

[0056] Preparation example Preparation Example 1 0.100 g of compound TJ0113 was weighed and 4 ml of acetone was added. The mixture was heated to approximately 45°C and stirred to dissolve. 0.223 g of a methanol solution of sodium methoxide was added dropwise at approximately 45°C. A small amount of solid precipitated upon addition, but it dissolved after stirring. After stirring, the solid gradually precipitated. The mixture was incubated at approximately 45°C for 1 hour. After incubation, it was cooled to approximately 20°C and stirred for 1 hour. The mixture was filtered by suction and rinsed with a small amount of acetone. It was vacuum-dried at room temperature (without heating) for approximately 20 hours. The crystalline form was determined to be D based on the following characterization method. TIFF2026511338000015.tif25170

[0057] Preparation Example 2 3.00 g of compound TJ0113 was weighed and 120 ml of acetone was added. The mixture was heated to approximately 45°C and stirred to dissolve. 5.20 g of 10% sodium bicarbonate aqueous solution was added dropwise at approximately 45°C. A small amount of solid precipitated upon addition, but it dissolved after stirring. After stirring, the solid gradually precipitated. The mixture was incubated at approximately 45°C for 1 hour. After incubation, it was cooled to approximately 20°C and stirred for 1 hour. The mixture was filtered by suction and rinsed with a small amount of acetone. It was vacuum dried at room temperature (without heating) for approximately 20 hours. The crystalline form was determined to be D based on the following characterization method. TIFF2026511338000016.tif21170

[0058] Characteristic evaluation X-ray diffraction: The crystal form D prepared above was analyzed using a PANalytacal empyrean powder X-ray diffractometer. The scanning parameters were as follows. TIFF2026511338000017.tif76170

[0059] Figure 8 shows the powder X-ray diffraction patterns of crystal form D prepared in Preparation Examples 1 and 2, and the peak positions and intensities of characteristic peaks are shown below. TIFF2026511338000018.tif181170

[0060] Differential scanning calorimetry and DSC spectroscopy: The prepared crystal form D was tested using a TA Q200 / 2000 differential scanning calorimetry instrument, and the test parameters were as follows: TIFF2026511338000019.tif44170

[0061] The DSC spectrum of crystal form D is shown in Figure 9. The differential scanning calorimetry curve of crystal form D shows an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C ±3°C.

[0062] Thermogravimetric analysis and TGA spectrum: The prepared crystal form D was tested using a TA Q500 / 5000 thermogravimetric analyzer, and the test parameters were as follows: TIFF2026511338000020.tif44170

[0063] The TGA spectrum of crystal form D is shown in Figure 10. The thermogravimetric analysis curve for crystal form D shows no weight loss of the sample before decomposition.

[0064] Examples The technical solutions and embodiments of the present invention are illustrated using capsules of compound TJ0113 as an example. It should be understood that these examples do not limit the scope of protection of the present invention, and in particular do not limit the active ingredient or specific dosage form. The “active ingredient” or “API” described in the examples is TJ0113, which is the solid form of the sodium salt of crystalline form D, prepared according to the above preparation example, with a batch number of A 16569-028P1 for the raw material product.

[0065] Example 1: Compatibility test between the active ingredient (API) and various auxiliary agents. The experimental procedure is as follows:

[0066] 1. Take samples according to the sampling timing set in the compatibility plan between raw materials and auxiliary agents (see Table 1).

[0067] 2. Record the appearance of the sample taken out. Abnormal appearances include (1) caking, (2) liquefaction, and (3) discoloration.

[0068] 3. Detect the increase in moisture-absorbing weight of the sample.

[0069] 4. Use HPLC to detect the content and related substances in the sample.

[0070] Details of the parameters for the HPLC method used to detect the content and related substances are shown in Table 2 below.

[0071] Adjuvants commonly used in oral solid dosage forms were selected, mixed with the TJ0113 active pharmaceutical ingredient (API) in different ratios, stored under different conditions, and removed at different time points. The compatibility between the API and the adjuvants was determined based on appearance, increase in weight due to moisture absorption, content, and related substances. According to the adjuvant manual, all adjuvants used are commonly used in oral solid dosage forms, are listed in the Chinese Pharmacopoeia, and the properties of each adjuvant are stable. To objectively evaluate the compatibility between the API and the adjuvants used, compatibility tests were conducted between the API and each adjuvant.

[0072] The ratio of active pharmaceutical ingredients (APIs) to adjuvants is based on the "Basic Technical Guidelines for Research on Chemical Pharmaceutical Formulations" and formulation standards. Adjuvants with high concentrations (such as lactose and microcrystalline cellulose) were mixed in a ratio of 1:5 for the active ingredient to the diluent. Adjuvants with moderate concentrations (such as cross-linked carboxymethylcellulose sodium) were mixed in a ratio of 1:1 for the active ingredient to the disintegrant. Adjuvants with low concentrations (such as magnesium stearate) were mixed in a ratio of 10:1 for the active ingredient to the lubricant. For manufacturer information on the APIs and adjuvants used in the conformity test, and the ratios of the APIs and adjuvants, please refer to Table 1 below.

[0073] TIFF2026511338000021.tif162170

[0074] TIFF2026511338000022.tif84170

[0075] The sample was subjected to high temperature (60°C), high humidity (92.5%RH), accelerated heating (40°C / 75%RH), and light irradiation (visible light 5500 Lux ± 500 Lux, near ultraviolet 85 μw / cm²). 2 The samples were placed under the specified test conditions, and samples were taken and evaluated on day 0, day 9, and day 30. The samples were submitted for relevant indicator tests (test items include appearance, increase in weight due to moisture absorption, content, and related substances), and the measurement results were compared with the control sample (active pharmaceutical ingredient). The relevant results are shown in Tables 3 to 9 below.

[0076] TIFF2026511338000023.tif244170TIFF2026511338000024.tif44170

[0077] TIFF2026511338000025.tif136170

[0078] TIFF2026511338000026.tif144170

[0079] The test results for the related substances are as follows:

[0080] [Table 6] Results for related substances under 60°C (open) conditions TIFF2026511338000027.tif230170TIFF2026511338000028.tif231170

[0081] [Table 7] Results for related substances under 40°C / 75%RH (open) conditions TIFF2026511338000029.tif250170TIFF2026511338000030.tif249170TIFF2026511338000031.tif250170

[0082] [Table 8] Results for related substances under 92.5%RH (open) conditions TIFF2026511338000032.tif247170TIFF2026511338000033.tif255170TIFF2026511338000034.tif255170

[0083] [Table 9] Results for related substances under light irradiation (aperture) conditions TIFF2026511338000035.tif246170TIFF2026511338000036.tif246170

[0084] The following is a discussion of experimental results regarding the compatibility of APIs with multiple adjuvants.

[0085] (1) Appearance: After being left open for 30 days under accelerated conditions of 40°C / 75%RH, the API and API mixed with other auxiliary agents turned into gray powder, except for the API + cross-linked polyvinylpyrrolidone XL-10 mixed sample, which turned into a red powder.

[0086] After being left open for 30 days under high humidity conditions of 92.5%RH, a mixed sample of API, API+Colloidal Silica AEROSIL(registered trademark) 200 Pharma, API+Magnesium Stearate LIGAMED MF-2-V-MB, API+Sodium Stearyl Fumarate, API+Talc Powder LUZENAC PHARMA, API+Gelatin Hollow Capsules, and 0# Opaque Dark Yellow (Cap Color Number: 41.813, Body Color Number: 41.813)-CN,US changed to a gray powder, while a mixed sample of API+Hydroxypropylcellulose EXF and API+Cross-linked Polyvinylpyrrolidone XL-10 changed to red.

[0087] After being left open for 30 days under high humidity conditions of 92.5%RH, a blocking phenomenon occurred in the mixed sample of API+pregelatinized starch STARCH 1500(registered trademark), API+hydroxypropylcellulose EXF, API+crosslinked polyvinylpyrrolidone XL-10, and API+carboxymethyl starch sodium VIVASTAR P.

[0088] After being left open for 10 days under light irradiation conditions, the surface of the API and the mixed sample of API and other auxiliary agents turned red, while the underlying layer did not change color.

[0089] Aside from this, no significant changes in appearance were observed in mixed samples of API and other adjuvants.

[0090] (2) Increase in weight due to moisture absorption After being left open for 30 days under high humidity conditions of 92.5%RH, a mixed sample of API, API+ microcrystalline cellulose 102, API+ pregelatinized starch STARCH 1500 (registered trademark), API+ hydroxypropyl cellulose EXF, API+ sodium carboxymethyl starch VIVASTAR P, API+ cross-linked sodium carboxymethylcellulose SD711, API+ cross-linked polyvinylpyrrolidone XL-10, API+ magnesium stearate LIGAMED MF-2-V-MB, and API+ gelatin hollow capsules 0# (opaque, dark yellow) showed a large increase in moisture-absorbing weight.

[0091] (3)Content The results show that there was no significant change in the content of API and mixed samples of API and each auxiliary agent after being left open for 30 days under high temperature of 60°C, high humidity of 92.5%RH and accelerated temperature of 40°C / 75%RH, and then left for 10 days under light irradiation conditions.

[0092] (4) Related substances After being left open for 30 days under high temperature conditions of 60°C, the API + mannitol 100SD mixed sample showed a slight increase in the relevant substances at RRT1.29 and RRT1.73.

[0093] A mixed sample of API + carboxymethyl starch sodium VIVASTAR P showed a slight increase in the relevant substance at RRT 1.29. A mixed sample of API + cross-linked polyvinylpyrrolidone XL-10 showed a slight increase in the relevant substance at RRT 0.46.

[0094] After being left open for 30 days under accelerated conditions of 40°C / 75%RH, the API showed a significant increase in the relevant substance at RRT0.46, RRT1.16, RRT1.63, and RRT1.73, and a slight increase at RRT1.41 and RRT1.43. The API + Lactose Tablettose 80 mixed sample showed a slight increase in the relevant substance at RRT0.89. The API + Mannitol 100SD mixed sample showed a slight increase in the relevant substance at RRT0.46, RRT0.89, RRT1.65 / 1.70, and RRT1.73. The API + Hydroxypropylcellulose EXF mixed sample showed a slight increase in the relevant substance at RRT0.46, RRT0.89, RRT1.10, RRT1.24, and RRT1.33, and a significant increase at RRT1.41. Mixed samples of API + carboxymethyl starch sodium VIVASTAR P showed a slight increase in the relevant substance at RRT 1.29. Mixed samples of API + cross-linked polyvinylpyrrolidone XL-10 showed a slight increase in the relevant substance at RRT 0.46, RRT 0.89, and RRT 1.10, and a significant increase at RRT 1.24, RRT 1.33, RRT 1.37, and RRT 1.41. Mixed samples of API + colloidal silica AEROSIL® 200 Pharma showed a significant increase in the relevant substance at RRT 0.46 and RRT 0.89. Mixed samples of API + magnesium stearate LIGAMED MF-2-V-MB showed a slight increase in the relevant substance at RRT 0.46 and RRT 1.63, and a significant increase at RRT 1.16 and RRT 1.73. Mixed samples of API + stearyl fumarate sodium showed a slight increase in the relevant substance at RRT 1.16. A mixed sample of API + talc powder from LUZENAC PHARMA showed a slight increase in the relevant substance at RRT1.73.

[0095] After being left open for 30 days under high humidity conditions of 92.5%RH, the API showed a significant increase in the relevant substance at RRT0.46, RRT1.16, RRT1.64, and RRT1.73, and a slight increase at RRT1.41 and RRT1.74. The API + mannitol 100SD mixed sample showed a significant increase in the relevant substance at RRT1.16. The API + hydroxypropylcellulose EXF mixed sample showed a significant increase in the relevant substance at RRT0.89, RRT1.10, RRT1.29, and RRT1.41, and a slight increase at RRT1.33. The API + cross-linked polyvinylpyrrolidone XL-10 mixed sample showed a significant increase in the relevant substance at RRT0.89, RRT1.10, RRT1.16, RRT1.29, and RRT1.41, and a slight increase at RRT1.33. Mixed samples of API + colloidal silica AEROSIL® 200 Pharma showed a significant increase in the relevant substance at RRT 0.46 and RRT 1.73, and a slight increase at RRT 1.54. Mixed samples of API + magnesium stearate LIGAMED MF-2-V-MB showed a significant increase in the relevant substance at RRT 1.16 and a slight increase at RRT 1.73. Mixed samples of API + sodium stearyl fumarate showed a slight increase in the relevant substance at RRT 1.16. Mixed samples of API + talc powder LUZENAC PHARMA showed a significant increase in the relevant substance at RRT 1.16 and a slight increase at RRT 1.21.

[0096] After being left open for 10 days under light irradiation conditions, the API showed a slight increase in the relevant substance at RRT 0.89 and RRT 1.29. The API + cross-linked carboxymethylcellulose sodium SD711 mixed sample showed a significant increase in the relevant substance at RRT 1.29. The API + cross-linked polyvinylpyrrolidone XL-10 and API + stearyl fumarate mixed samples showed a slight increase in the relevant substance at RRT 1.29. The API + talc powder LUZENAC PHARMA mixed sample showed a significant increase at RRT 1.16 and a slight increase in the relevant substance at RRT 1.73.

[0097] In summary, as can be seen from the compatibility tests of the active pharmaceutical ingredient and adjuvants, APIs are unstable under high humidity, light irradiation, and accelerated conditions. Mixed samples of API with hydroxypropylcellulose EXF, cross-linked polyvinylpyrrolidone XL-10, colloidal silica AEROSIL® 200 Pharma, and magnesium stearate LIGAMED MF-2-V-MB were incompatible under accelerated conditions of 40°C / 75%RH and high humidity conditions of 92.5%RH. Mixed samples of API with talc powder LUZENAC PHARMA were incompatible under high humidity conditions of 92.5%RH, with open aperture and light irradiation. Mixed samples of API with mannitol 100SD were sometimes incompatible under high humidity conditions of 92.5%RH. Mixed samples of API + cross-linked carboxymethylcellulose sodium SD711 were sometimes incompatible under light irradiation conditions.

[0098] Example 2: Effect of diluent on dissolution performance Considering that TJ0113 itself is unstable under high humidity conditions, the influence of the type of diluent on the preparation process and capsule dissolution was examined based on the compatibility test results of the active pharmaceutical ingredient and the adjuvant. The dissolution methods used to measure the dissolution rate in this application are shown in Table 10.

[0099] TIFF2026511338000037.tif78170

[0100] In this example, 100 mg capsules were the main subject of study, with a total weight of 420 mg of contents. Opaque, dark yellow gelatin hollow capsules were used, and all capsules were filled with granules produced by a drying method. Table 11 shows the specific components of experiments F6 and F7, which used different types of diluents. The effect of the type of diluent on the dissolution results is shown in Table 12 and Figure 1, and dissolution method 1 was used for evaluation.

[0101] TIFF2026511338000038.tif123170

[0102] TIFF2026511338000039.tif43170

[0103] As shown in Figure 1, the elution of F7 was significantly higher than that of F6 (especially within the first 20 minutes), indicating that the combination of microcrystalline cellulose and pregelatinized starch unexpectedly improved the elution rate of this API. Therefore, the diluents used were microcrystalline cellulose 102 and pregelatinized starch STARCH 1500 (registered trademark).

[0104] The API of this invention shows a significant increase in related substances under high humidity conditions, therefore, pregelatinized starch STARCH 1500 (registered trademark) (Zentatsu) TM ) can absorb free moisture that has entered the core and retain moisture, thereby preventing interaction with drugs. Therefore, the effect of different formulation ratios of pregelatinized starch STARCH 1500 (registered trademark) on product dissolution was also investigated. The specific compositions are shown in Table 13, and the dissolution results are shown in Table 14 and Figure 2, with dissolution method 2 used for evaluation.

[0105] TIFF2026511338000040.tif107170

[0106] TIFF2026511338000041.tif43170

[0107] The elution results showed no significant difference between F11 and F12, indicating that the proportion of pregelatinized starch did not significantly affect the elution rate. Therefore, it was ultimately decided to use 25 wt% pregelatinized starch STARCH 1500 (registered trademark) for subsequent process development.

[0108] Example 3: Effects of disintegrants and solubilizers on elution results Based on the experimental results of Example 2, the type of disintegrant was investigated using the capsule dissolution rate as an indicator. The specific compositions of experiments F7 and F10 are shown in Table 15. Of these, F10 had a different type of disintegrant, while the other conditions were the same as in Example 2. The dissolution results are shown in Table 16 and Figure 3, and dissolution method 2 was used for evaluation.

[0109] TIFF2026511338000042.tif110170

[0110] TIFF2026511338000043.tif43170

[0111] From the above results, it can be seen that experiment F10 showed slightly higher elution at 30 minutes prior than F7, and a lower RSD%. Therefore, the type of disintegrant was determined to be carboxymethyl starch sodium VIVASTAR P.

[0112] Based on these results, the effect of adding a solubilizer on the product's elution rate was further investigated. The compositions of F7 and F8 are shown in Table 17, with a solubilizer added to F8, and the other conditions being the same as in Example 2. The elution results are shown in Table 18 and Figure 4, and elution method 2 was used for evaluation.

[0113] TIFF2026511338000044.tif109170

[0114] TIFF2026511338000045.tif43170

[0115] From the results above, it was found that there was no significant difference in the elution results between experiments F7 and F8, indicating that the addition of the solubilizer, sodium lauryl sulfate Kolliphor SLS Fine, did not have a significant effect on the elution rate. Therefore, it was ultimately confirmed that sodium lauryl sulfate Kolliphor SLS Fine should not be used as a solubilizer.

[0116] The 20mg and 100mg capsules were formulated in equal proportions, and the manufacturing process was nearly identical. The composition and dissolution results (evaluated by dissolution method 3) of the 20mg capsules are shown in Tables 19, 20, and Figure 5.

[0117] TIFF2026511338000046.tif112170

[0118] TIFF2026511338000047.tif30170

[0119] The data above shows that the 20mg capsules dissolve rapidly and completely, which was expected and indicates that its specific compositional design is reasonable.

[0120] Example 4: Overall Stability Test of the Formulation The process procedure for the formulation in this embodiment is as follows: API and microcrystalline cellulose 102 were sieved through a 50-mesh sieve; the sieved API and microcrystalline cellulose 102 were sieved twice with pregelatinized starch STARCH 1500 (registered trademark) through a 50-mesh sieve; the sieved API, microcrystalline cellulose 102, pregelatinized starch STARCH 1500 (registered trademark), and sodium carboxymethyl starch VIVASTAR P were pre-mixed; sodium stearyl fumarate was added internally to the pre-mixed material and the main mixing was performed; after the main mixing was completed, dry granulation was performed; sodium stearyl fumarate was added externally to the dry-granulated material and the total mixing was performed; and finally, the total mixed granules were filled into capsules.

[0121] The specific process steps and parameters are as follows: 1. Weighing According to the prescribed dosage, TJ0113, microcrystalline cellulose 102, pregelatinized starch STARCH 1500 (registered trademark), sodium carboxymethyl starch VIVASTAR P, and sodium stearyl fumarate were weighed out.

[0122] 2. Sieving First, microcrystalline cellulose 102 and the active pharmaceutical ingredient were sieved once using a 50-mesh sieve to obtain sieved mixture 1; next, sieved mixture 1 and pregelatinized starch STARCH 1500 (registered trademark) were sieved twice using a 50-mesh sieve; carboxymethyl starch sodium VIVASTAR P was sieved using a 50-mesh sieve, and the internally and externally added stearyl fumarate sodium were each sieved using a 30-mesh sieve.

[0123] 3. Pre-mixing The active pharmaceutical ingredients and auxiliary agents other than sodium stearyl fumarate were placed in the hopper of a hopper mixer and mixed at a mixing speed of 20 rpm for 20 minutes.

[0124] 4. Book mixture After the preliminary mixing was complete, sodium stearyl fumarate (added internally) was added to the hopper, and the main mixing was started, with the mixture being mixed at a mixing speed of 20 rpm for 5 minutes.

[0125] 5. Dry granulation and sizing The main mixed powder was placed in a dry granulator and granulated. The granulation parameters were a feeding speed of 28 rpm and a roll pressure of 30 kg / cm². 2 The roll rotation speed was set to 8 rpm. The strip material obtained by drying and granulating was crushed, and a circular sieve with a mesh size of 0.8 mm was used for secondary sizing, with a sizing rotation speed of 150 rpm.

[0126] 6. Total mixing The dried granules after granulation and the sieved sodium stearyl fumarate (added externally) were placed in the hopper of a hopper mixer and mixed for 5 minutes at a mixing rotation speed of 20 rpm.

[0127] 7. Capsule filling The total mixed granules were placed into a capsule filling machine, and capsules were filled. The 20 mg formulation was filled into #4 gelatin hollow capsule shells, and the 100 mg formulation was filled into #0 gelatin hollow capsule shells.

[0128] Initial stability testing in the laboratory Initial stability tests were conducted on laboratory samples to evaluate the rationality and stability of the prototype formulation.

[0129] The sample batches used for stability testing were F14 and F13, and their specific compositions and sample information are shown in Tables 21 and 22.

[0130] TIFF2026511338000048.tif135170

[0131] TIFF2026511338000049.tif58170

[0132] The storage conditions for samples F13 and F14 of the two standards were the same. The specific storage conditions are shown in Table 23.

[0133] TIFF2026511338000050.tif55170

[0134] The elution results from the stability test are shown in Table 24 and Figures 6 and 7, and the results for related substances in the stability test are shown in Table 25.

[0135] TIFF2026511338000051.tif117170

[0136] Results Analysis: Based on the above data, compared to the dissolution data for day 0, no significant changes were observed in the dissolution of the 20 mg and 100 mg capsules after being left for 30 days under conditions of 40°C / 75% RH (closed) and 40°C / 75% RH (closed + 2 g desiccant).

[0137] [Table 25] Results (%) of stability-related substances for 20 mg and 100 mg capsules TIFF2026511338000052.tif244170

[0138] Results Analysis: After leaving 20mg capsules at 40°C / 75%RH (closed) for 30 days, the relevant substance increased at RRT=1.16, RRT=1.37 / 1.38, and RRT=1.82 / 1.73. After leaving 100mg capsules at 40°C / 75%RH (closed) for 30 days, the relevant substance increased at RRT=1.37 / 1.38. No significant changes in the relevant substance were observed after leaving 20mg and 100mg capsules under other conditions for 30 days.

[0139] After comprehensively reviewing the dissolution test and related substance test results, the final product packaging was decided to consist of 45mL and 75mL high-density polyethylene bottles for oral solid medicines, polypropylene child-safe combination caps with aluminum foil seals, and two solid medicine paper bags (with English labeling) containing 1g of silica gel desiccant. The storage conditions were set to "protect from light, sealed, and stored at 2-8°C."

[0140] Example 5: Effect of dry granulation on the crystal structure of the active pharmaceutical ingredient In this study, the effect of dry granulation on the crystalline form of the active pharmaceutical ingredient (API) was investigated. The formulation composition is shown in Table 21, F13, and the XRPD results are shown in Figure 9. The XRPD procedure was the same as in the preparation example. The obtained XRPD spectra are shown in Figure 11, where curve A16569-028P1 represents the API; curve 41458-088-14 / 13-20 / 100mg-BL represents the mixed powder before dry granulation; curve 41488-011-14 / 13-20 / 100mg-BL-BE represents the blanking agent before dry granulation; and curve 41458-088-14 / 13-20 / 100mg-DG-4 represents the dried granules after dry granulation. From the curves above, it can be seen that there is no significant change in the major characteristic peaks of the XRPD spectra of the intermediate active samples before and after dry granulation. This led to a preliminary conclusion that the dry granulation process does not affect the crystal structure of the active pharmaceutical ingredient.

Claims

1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, or a lubricant, but not containing any of hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, colloidal silica, magnesium stearate, talc powder, mannitol, or cross-linked carboxymethylcellulose sodium. (In the formula, R ２ is hydrogen, C １～４ Alkyl, C ３～６ They are cycloalkyl or 4-6 member epoxyalkyl groups; R ３ teeth And; Here, R ３－１ is hydrogen, hydroxyl, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, 3- to 6-membered epoxyalkyl, -N(R ３－２ R ３－２ａ ), -CH ２ C(O)R ３－２ 、-CH ２ C(O)OR ３－２ 、-CH ２ C(O)NR ３－２ R ３－２ａ and R ３－２ and R ３－２ａ Each is independently hydrogen, C １～４ Alkyl or 3-6 member cycloalkyl, Ar is phenyl, a 5-membered or 6-membered monocyclic heteroaryl, and at least one R ３－３ A five-membered or six-membered monocyclic heteroaryl substituted with the R ３－３ is hydrogen, halogen, C １～４ Alkyl, 3-6 member cycloalkyl, hydroxy, C １～４ Alkoxy, 3- to 6-membered epoxyalkyl, C １～４ Haloalkyl, C ２～４ Alkenil, C ２～４ Alkinyl, -N(R) ３－３ａ R ３－３ｂ ) or phenyl, R ３－３ａ and R ３－３ｂ Each is independently hydrogen, C １～４ Alkyl or 3-6 membered cycloalkyl; R ４ teeth And, Here, R ４－１ is phenyl, at least one R ４－１１ Phenyl substituted with, 5-membered or 6-membered monocyclic heteroaryl, at least one R ４－１１ A 5- or 6-membered monocyclic heteroaryl substituted with, an 8- to 10-membered fused bicyclic heteroaryl, or at least one R ４－１１ It is an 8- to 10-membered condensed bicyclic heteroaryl substituted with the R ４－１１ is halogen, nitro group, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, -N(R ４－１ａ R ４－１ｂ ), phenyl, C １～４ Haloalkyl, C １～４ Haloalkoxy, or And R ４－１ａ and R ４－１ｂ Each is independently hydrogen, C １～４ Alkyl or C ３～６ It is a cycloalkyl, R ４－１ａ and R ４－１ｂ They may be joined to each other to form a ring. R ４－２ C １～４ Alkyl, C ３～６ It is cycloalkyl, or R ２ C １～４ If it is alkyl, R ４－２ is R ２ It bonds to form a 4-8 membered ring, R ４－３ is C １～４ Alkyl or C １～４ It is an alkoxy; R ５ The number of R is from 0 to 5. When the number of R ５ is not 0, each R ５ is independently selected from halogen, nitro group, nitrile group, -N ＋ (R ５－１ ) ３ , C １～４ haloalkyl, -C(O)OR ５－１ , -C(O)R ５－１ , -C(O)N(R ５－１ R ５－１ａ ), -S(O) ２ R ５－１ , -S(O)R ５－１ , -N = C(R ５－１ R ５－１ａ ), hydroxy, C １～４ alkyl, phenyl, phenyl with at least one hydrogen substituted by R ５－１ , C １～４ alkoxy, -N(R ５－１ R ５－１ａ ), -N(R ５－１ )C(O)R ５－１ａ , -OC(O)R ５－１ , -OC(O)N(R ５－１ R ５－１ａ ), or -SR ５－１ . Here, R ５－１ , R ５－１ａ and R ５－１ｂ are each independently hydrogen, C １～４ alkyl, C ２～４ alkenyl, C ２～４ alkynyl, C １～４ alkyl with at least one hydrogen substituted by halogen, C ２～４ alkenyl with at least one hydrogen substituted by halogen, or C ２～４ alkynyl with at least one hydrogen substituted by halogen. )

2. The pharmaceutical composition according to claim 1, wherein the compound of formula (1) is TJ0113.

3. The pharmaceutical composition according to claim 2, wherein TJ0113 is a solid form of a sodium salt represented by the following formula. (In the formula, X is between 0.1 and 2, for example, 1.)

4. The pharmaceutical composition according to claim 3, wherein the powder X-ray diffraction pattern of the solid form shows characteristic peaks (CuKα lines) at 2θ of 7.06° (±0.2°) and 20.87° (±0.2°).

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

6. The pharmaceutical composition according to claim 5, comprising compound TJ0113 or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and sodium stearyl fumarate.

7. A pharmaceutical composition according to any one of claims 1 to 4, wherein the percentage of compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1.0% to 50% by weight, the percentage of diluent in the pharmaceutical composition is 30% to 90% by weight, the percentage of disintegrant in the pharmaceutical composition is 0.1% to 25% by weight, and the percentage of lubricant in the pharmaceutical composition is 0.01% to 5.0% by weight.

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